1. Topic #2: Quality by Design and Pharmaceutical Equivalence Ajaz S. Hussain, Ph.D. Office of Pharmaceutical Science Center for Drug Evaluation and Research Food and Drug Administration ACPS Meeting May 2005

2. ACPS May 2005 199519972000 SUPACDissolution IVIVC BCS ICH Q6A 2004, PAT & draft ICH Q8 Current State Desired State

3. From a “Reactive” to a “Proactive” Decision System for Pharmaceutical Quality Reactive (examples)  Testing to document quality  Repeating deviation and out of specification investigations  Prior Approval Supplement for process optimization and continuous improvement efforts  Multiple CMC review cycles  Procrustean approach for demonstrating therapeutic equivalence of generic products Proactive (examples)  Quality by design and “real time release”  Right First Time  Process optimization and continuous improvement efforts within a facilities quality system  Single CMC review cycle and risk-based specifications  QbD approaches for demonstrating therapeutic equivalence of generic products This is a journey and not a destination!

4. Therapeutic Equivalence Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling. The Orange Book

5. Pharmaceutical Equivalent Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration (e.g., chlordiazepoxide hydrochloride, 5mg capsules). Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity), but they may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration time, and, within certain limits, labeling. The Orange Book

6. FDA classifies as Therapeutically Equivalent those products Approved as safe and effective Pharmaceutical equivalents in that they  contain identical amounts of the same active drug ingredient in the same dosage form and route of administration, and  meet compendial or other applicable standards of strength, quality, purity, and identity;  are bioequivalent in that they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard;  are adequately labeled; and  are manufactured in compliance with Current Good Manufacturing Practice regulations. The Orange Book

7. Components of the Challenge Risk-based scientific decisions on pharmaceutical quality  Risk: combination of the probability of occurrence of harm and the severity of that harm  Uncertainty with respect to severity of harm and/or probability of its occurrence and their modulating factors (e.g., critical quality attributes, variability,..)

8. Confounding of Uncertainty, Variability, and Risk Product and process development paradigm Approval decision: “Risk/Benefit ratio”  Often intrinsic safety & efficacy of an NME confounded with its product and manufacturing process Multi-factorial aspect of pharmaceutical products and manufacturing processes; increasing complexity Establishing “constraints” based on prior knowledge and limited development experiments (time and material constraints)

9. The Pharmaceutical Quality “Paradox” “A need exists first to untangle or de- convolute uncertainty – variability – risk and then to achieve a scientific (re) integration of these for quality decisions (e.g., regulatory application approval decisions). This may appear to be paradoxical, and it probably is without the concept of quality by design (QbD).” Ajaz Hussain. Process Analytical Technology: A First Step in a Journey towards the Desired State. The Journal for Process Analytical Technology. January 2005.

10. Risk/Benefit and Quality Harm AcceptableRisk/Benefit Quality Label No benefit (placebo effect) Quality Clinical Trial Product Production lots Patient population Clinical Trial

11. In Vivo BE* for Justifying Changes During Development Capsule Tablet (WG) Film Coat Site Change in Drug Manuf. Solvent -Coat Site Change Tablet (DC) Multi- Strength Scale-up Multi- Strength BE Study Failed BE To-Be-Marketed Approval *Generally 3-6 clinical bioequivalence tests are conducted in a NDA

12. Average # of BE Studies: At a Major Pharmaceutical Company mean ~ 24 mean ~ 7

14. Goal: approved generic product is expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling CharacteristicsUncertaintyVariabilityRisk Pharmaceutical Equivalent Same active, identical amount, same dosage form, and route of administration. Identity, Strength Quality, Purity. Compendial or other standards Prior Knowledge (NDA) Post Approval: Monitoring program Such as MedWatch Consumer Complaints Therapeutic Inequivalence Coordinating Committee Need for Bioequivalence Assessment Do not present a known or potential bioequivalence problem. Acceptable in vitro standard Compendial Dissolution test method Present a known or potential bio -problem. Appropriate bioequivalence standard 90% Confidence Interval of Test/Ref ratio for rate and extent of absorption in 80 -125% range Adequately Labeled Similarity with reference label, medication errors.,, Certain differences due to changes in the manufacturer, distributor, pending exclusivity issues, or other characteristics Manufactured in conformance to CGMP's Process Validation and Quality System Deviations, Out of Specifications,...

15. Design is about doing things consciously Intended Use Route of administration Patient population ….. Product Design Design Specifications (Customer requirements) Manufacturing Process Design and Control Capability Ability to reliably and consistently deliver the target product design specifications ProductPerformance: Design specifications reliably and consistently deliver the therapeutic objectives

16. Points to consider….. In the context of pre/post-approval changes, generic drugs, and the concept of follow-on protein pharmaceuticals, the primary goal of a scientific decision framework should be to ensure that an approved product is expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling  Furthermore – identifying and elimination (or minimizing) unnecessary human and animal testing are also the goals of this decision framework

17. Topic #2: Premise A QbD approach via pharmaceutical development information can potentially provide an excellent means to address a number of challenges previously discussed at ACPS meetings without complete or satisfactory resolution – for example:  bioequivalence of highly variable drugs, bio-in-equivalence criteria, pharmaceutical and therapeutic equivalence of locally acting drug products (e.g., topical drug products).  In addition, further elaboration and extended application of the Biopharmaceutics Classifications System (BCS)-based waiver of in vivo bioequivalence is essentially an extension of Topic #1 discussions.

18. Our initial thoughts – Are we on the right tract? How can pharmaceutical development information help to extend the applications of BCS-based waiver of in vivo studies for immediate release products? How can pharmaceutical development information be utilized to address the challenge of highly variable drugs? Establishing therapeutic equivalence of topical products?